Department of Veterinary Microbiology and Pathology, College of Veterinary Medicine, Washington State University, Pullman, Washington, United States of America.
Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center, Boston, Massachusetts, United States of America.
PLoS Pathog. 2020 May 26;16(5):e1008600. doi: 10.1371/journal.ppat.1008600. eCollection 2020 May.
Apicomplexan parasites cause severe disease in both humans and their domesticated animals. Since these parasites readily develop drug resistance, development of new, effective drugs to treat infection caused by these parasites is an ongoing challenge for the medical and veterinary communities. We hypothesized that invertebrate-bacterial symbioses might be a rich source of anti-apicomplexan compounds because invertebrates are susceptible to infections with gregarines, parasites that are ancestral to all apicomplexans. We chose to explore the therapeutic potential of shipworm symbiotic bacteria as they are bona fide symbionts, are easily grown in axenic culture and have genomes rich in secondary metabolite loci [1,2]. Two strains of the shipworm symbiotic bacterium, Teredinibacter turnerae, were screened for activity against Toxoplasma gondii and one strain, T7901, exhibited activity against intracellular stages of the parasite. Bioassay-guided fractionation identified tartrolon E (trtE) as the source of the activity. TrtE has an EC50 of 3 nM against T. gondii, acts directly on the parasite itself and kills the parasites after two hours of treatment. TrtE exhibits nanomolar to picomolar level activity against Cryptosporidium, Plasmodium, Babesia, Theileria, and Sarcocystis; parasites representing all branches of the apicomplexan phylogenetic tree. The compound also proved effective against Cryptosporidium parvum infection in neonatal mice, indicating that trtE may be a potential lead compound for preclinical development. Identification of a promising new compound after such limited screening strongly encourages further mining of invertebrate symbionts for new anti-parasitic therapeutics.
顶复门寄生虫可引起人类和家养动物的严重疾病。由于这些寄生虫容易产生耐药性，因此开发新的、有效的药物来治疗这些寄生虫引起的感染，是医学和兽医界面临的持续挑战。我们假设无脊椎动物-细菌共生体可能是抗顶复门化合物的丰富来源，因为无脊椎动物容易受到原顶复门寄生虫——血孢子虫的感染。我们选择探索船蛆共生细菌的治疗潜力，因为它们是真正的共生体，容易在无菌培养中生长，并且基因组中富含次生代谢物基因座[1,2]。两种船蛆共生细菌——特氏杆菌（Teredinibacter turnerae）被筛选出对刚地弓形虫的活性，其中一种菌株 T7901 对寄生虫的细胞内阶段表现出活性。基于生物活性的分离鉴定出 tartrolon E（trtE）是活性的来源。TrtE 对刚地弓形虫的 EC50 为 3 nM，直接作用于寄生虫本身，在治疗两小时后杀死寄生虫。TrtE 对隐孢子虫、疟原虫、巴贝斯虫、泰勒虫和肉孢子虫具有纳摩尔至皮摩尔级的活性；这些寄生虫代表了顶复门系统发育树的所有分支。该化合物对新生小鼠的微小隐孢子虫感染也有效，表明 trtE 可能是临床前开发的潜在先导化合物。在如此有限的筛选后鉴定出有前途的新化合物，强烈鼓励进一步挖掘无脊椎动物共生体以开发新的抗寄生虫治疗药物。
